Abstract

Background

To evaluate transitions in causes of death in patients with renal replacement therapy (RRT) since childhood over time, we performed a 10-year extension of the Late Effects of Renal Insufficiency in Children (LERIC) study.

Methods

The LERIC cohort consisted of all 249 Dutch patients, who were born before 1979 and started RRT <15 years of age between 1972 and 1992. We collected data on mortality and causes of death over the period 2000–10 and compared them with the previously gathered data over the period 1972–99.

Results

The median duration of follow-up from the start of RRT was 25.5 (range 0.3–39.0 years). Overall, 97 patients died of whom 34 in 2000–10. The overall mortality rate and mortality rate ratios (MRRs) stabilized over time. The MRR for cardiovascular death decreased from 660 in 1972–89 to 70 in 1990–99 and to 20 in 2000–10. Conversely, the MRR for infectious death showed a U-shape; it decreased from 503 in 1972–89 to 102 in 1990–99 and increased again to 350 in 2000–10. In 2000–10, infections became the most prevalent cause of death (44%). In 2000–10, the cardiovascular mortality had decreased with 91% since 1972–89 [adjusted hazard ratio (HR): 0.09, 95% confidence interval (95% CI): 0.02–0.45, P = 0.003], while infectious mortality had doubled over time, although not significantly (adjusted HR: 2.12, 95% CI: 0.88–5.11, P = 0.09).

Conclusions

Over the last decade, we found a substantial shift from cardiovascular disease to infections as the main cause of death at long-term follow-up in patients with chronic kidney disease since childhood and who were born before 1979.

INTRODUCTION

Few data exist on the very long-term outcome of patients with chronic kidney disease (CKD). Between 1998 and 2000, we conducted a comprehensive study to evaluate the Late Effects of Renal Insufficiency (LERIC) in all Dutch children who had started chronic renal replacement therapy (RRT) at <15 years of age between 1972 and 1992. Previous analyses of this cohort including data up to the year 2000 showed that, in this age category, patients with CKD had a 31-fold increased risk of mortality when compared with the general population [1], and that cardiovascular disease was by far the most important cause of death among both the dialysis patients and transplant recipients, accounting for 41% of all deaths [1, 2].

Our findings were confirmed by McDonald and Craig [3], who found a similar mortality risk in patients from Australia and New Zealand who started RRT before the age of 20 years between 1962 and 2000. They found the equally high percentage of 45% of all deaths being contributed to cardiovascular disease [3]. Among the survivors in the LERIC cohort in 1999, we also found a high prevalence of cardiovascular disease, which was reflected by an overall increased mean arterial wall stiffness, left ventricular hypertrophy in 40% and aortic calcifications on ultrasound in 19% of patients [2]. In 2002, Oh et al. [4] showed similar cardiovascular abnormalities in young adults with chronic renal failure since childhood and treated with RRT, including a high prevalence of calcifying arteriopathy. Coronary calcifications were observed in 92% of patients, and carotid intimae media thickness was significantly increased compared with matched controls [4].

Given this high prevalence of cardiovascular disease among the survivors of RRT since childhood and a possible further increase due to advancing age, we expected cardiovascular death to become an even more pronounced problem after 2000. We conducted an extended follow-up study of this cohort to investigate the actual trend in long-term mortality and causes of death after 2000.

SUBJECTS AND METHODS

Study design

The LERIC cohort comprised all Dutch patients who had started chronic RRT at <15 years of age between 1972 and 1992, and who were born before 1979. In 1998 and 2000, the first follow-up study of these 249 patients was conducted, which was described in detail previously [1]. In 2010, a second follow-up study was conducted covering the period from the last chart review in 1999 until the last chart review in 2010–11 or the patient's death. In this paper, we analysed data on mortality and causes of death in the total cohort from 1972 until 2010 and compared two time periods, 1990 until 1999 and 2000 until 2010, with the time period 1972 until 1989. We obtained permission from the medical ethical committee and informed consent from all patients who were alive in 2000.

Data collection

For the second follow-up period, we reviewed medical charts from all patients between 1 June 2010 and 1 February 2011. We attempted to localize all emigrated patients. Among others, we collected data on the cause of death, total duration of haemodialysis (HD), peritoneal dialysis (PD) and transplantation (Tx), age at death and modality of RRT at the time of death. In living patients, the day of review was considered as the end of the observation period for that particular patient.

Categorization of causes of death

Causes of death were categorized independently by three reviewers (J.L.V., J.W.G. and K.J.J.), using detailed description of all available data around the patient's time of death. After assessment of interobserver variability, consensus was achieved by discussion. When after discussion the patient's cause of death was still unclear, the patient's nephrologist was contacted to obtain information on the cause of death. As a reference, mortality data from the Dutch general population were used, which were obtained from the Dutch Office of Death Statistics [5].

Statistical analysis

The mortality rate (MR) was calculated as the number of deaths per 100 patient years (pys) on RRT with a 95% confidence interval (95% CI). The mortality rate ratios (MRRs) were calculated to compare mortality in RRT patients with that in the general population. The MRR was defined as the MR for a certain cause of death in RRT patients divided by the MR in the Dutch general population for the same cause of death thereby adjusting for age and time period. We used the Cox proportional hazards model (adjusted for age and gender-related general population mortality: background mortality) to analyse whether the risk of death for overall, cardiovascular and infectious mortalities changed over the time periods 1990–99 and 2000–10 when compared with the time period 1972–89.

RESULTS

Study population

The total cohort consisted of 249 patients (Table 1). Only 3 of the 249 patients (1.2%) were lost to follow-up. The median age at the start of RRT was 11.2 (range 1.9–15.0 years) and 54.6% were males (Table 1). The median age of survivors was 28.9 (range 21.0–40.9 years) in 1999 and 40.0 (range 31.6–50.8 years) in 2010. The median total follow-up time was 25.5 (range 0.3–39.9 years), time on haemodialysis 2.3 (range 0.03–36.5 years), time on peritoneal dialysis 2.4 (range 0.01–18.6 years) and time living with a renal graft 19.7 (range 0.0.1–39.3 years; Table 1). Among the 231 (93%) transplant recipients, 71 (31%) lived with a single transplant—not necessarily their first—for more than 20 consecutive years and up to 37.2 years (Table 1).

Table 1:

Main characteristics of the cohort between 1972 and 2010

1972 – 2010 N Median (range)in years Treatment duration in years, median (range) 
Male (%) 136 (54.6%)   
Age at the start of RRT 249 11.2 (1.9–15.0)  
Total follow-up time on RRT 249  25.5 (0.3–39.9) 
HD: patients with at least 1 period of HD 236  2.3 (0.03–36.5) 
HD: patients who had HD for >10 years 33  12.9 (10.2–36.5) 
PD: patients with at least 1 period of PD 101  2.4 (0.01–18.6) 
PD: patients who had PD for >10 years  11.2 (10.1–18.6) 
Tx: patients with at least 1 period of Txa 231  19.7 (0.01–39.3) 
Tx: patients who had Tx for >20 years (combined) 114  26.1 (20.0–39.3) 
Tx: patients who had one Tx for >20 consecutive years 71  25.6 (20.1–37.2) 
1972 – 2010 N Median (range)in years Treatment duration in years, median (range) 
Male (%) 136 (54.6%)   
Age at the start of RRT 249 11.2 (1.9–15.0)  
Total follow-up time on RRT 249  25.5 (0.3–39.9) 
HD: patients with at least 1 period of HD 236  2.3 (0.03–36.5) 
HD: patients who had HD for >10 years 33  12.9 (10.2–36.5) 
PD: patients with at least 1 period of PD 101  2.4 (0.01–18.6) 
PD: patients who had PD for >10 years  11.2 (10.1–18.6) 
Tx: patients with at least 1 period of Txa 231  19.7 (0.01–39.3) 
Tx: patients who had Tx for >20 years (combined) 114  26.1 (20.0–39.3) 
Tx: patients who had one Tx for >20 consecutive years 71  25.6 (20.1–37.2) 

aNumber of renal transplants per patient: median (range), 2 (0–6).

Ninety-two patients received only a single renal allograft (39.8%). Transplantation was performed two times in 84 (36.4%) patients, three times in 43 (18.6%), four times in 8 (3.5%), five times in 1 (0.4%) and six times in 3 (1.3%). Patients changed treatment modality between 1 and 11 times during the study period. Of the 249 patients, only 2 (0.8%) patients lived on a functioning graft during their entire follow-up (median survival 25.3 years) and 18 (7.2%) only received dialysis (median survival 3.7 years).

Of the 186 patients who were still alive in 2000, 79% had a functioning renal graft, similar to the proportion of the 152 patients who were still alive in 2010 (80%).

Mortality and causes of death

Of all 249 patients, 42 died between 1972 and 1989, 21 between 1990 and 1999 and 34 between 2000 and 2010. The overall (1972–2010) MR was 1.69/100 patient-years. The median age at the time of death was 22.8 (range 4.2–46.24 years). In the last decade, 12 of the patients died from cardiovascular disease, 44 from infections, 20.5 from malignancies, 20.5 from other causes and 3% (1 case) from unknown cause. Most patients died while on dialysis (53%; Supplementary material, Appendix 1). Of those who died of cardiovascular disease, 75% received dialysis at the time of death; of those who died of infections, this was 60%. Of those who died of infections in the last decade, one-third died of PD-related peritonitis.

Changes in the patterns of the cause of death

Table 2 presents the MRs and the MRRs for the overall causes of death in the periods 1972–89, 1990–99 and 2000–10, divided into five categories: cardiovascular, infections, malignancies, other and unknown. The all-cause crude MR did not significantly change over time. The cardiovascular MR decreased significantly from 0.97/100 per py (95% CI: 0.58–1.51) in 1972–89 to 0.22/100 py (95% CI: 0.06–0.56) in 2000–10. In contrast, the infection-associated MR did not significantly change over time from 0.51/100 py in 1972–89 (95% CI: 0.24–0.94) to 0.82/100 py (95% CI: 0.46–1.35) in 2000–10. The MR for malignancies, other and unknown causes of death did not change over time (Table 2). We saw the same trends in MR for the different causes of death when we calculated the MR for dialysis patients and transplant recipients separately.

Table 2:

MRs (deaths/100 pys) and MRR (MR in patients/MR in age- and gender-related general population) over three time periods

 1972–89 (95% CI) 1990–99 (95% CI) 2000–10 (95% CI) 
Mortality rate    
 All causes 2.14/100 py (1.54–2.89) 1.11/100 py (0.69–1.70) 1.86/100 py (1.29–2.60) 
 Cardiovascular 0.97/100 py (0.58–1.51) 0.37/100 py (0.15–0.76) 0.22/100 py (0.06–0.56)* 
 Infection 0.51/100 py (0.24–0.94) 0.32/100 py (0.12–0.70) 0.82/100 py (0.46–1.35) 
 Malignancy 0.20/100 py (0.05–0.51) 0.11/100 py (0.01–0.40) 0.38/100 py (0.15–0.78) 
 Other 0.41/100 py (0.18–0.81) 0.32/100 py (0.12–0.70) 0.38/100 py (0.15–0.78) 
 Unknown 0.05/100 py (0.00–0.28) 0/100 py (0.00–0.00) 0.05/100 py (0.00–0.28) 
Mortality rate ratio 
 All causes 53.0 (36.9–69.1) 19.7 (10.8–28.6) 26.8 (17.8–35.8) 
 Cardiovascular 660.3 (368.1–952.5) 70.0 (14.0–126.0) 19.6 (0.5–38.7) 
 Infections 502.5 (177.5–827.5) 101.8 (14.1–189.5) 352.6 (174.0–531.2) 
 Malignancies 29.2 (12.3–46.1) 18.8 (8.0–29.6) 18.5 (11.5–25.5) 
 Other 17.1 (5.9–28.2) 8.6 (1.0–16.2) 12.8 (3.4–22.2) 
 Unknown 19.9 (0.9–38.9) 0 (0.0–0.0) 10.5 (0.3–20.7) 
 1972–89 (95% CI) 1990–99 (95% CI) 2000–10 (95% CI) 
Mortality rate    
 All causes 2.14/100 py (1.54–2.89) 1.11/100 py (0.69–1.70) 1.86/100 py (1.29–2.60) 
 Cardiovascular 0.97/100 py (0.58–1.51) 0.37/100 py (0.15–0.76) 0.22/100 py (0.06–0.56)* 
 Infection 0.51/100 py (0.24–0.94) 0.32/100 py (0.12–0.70) 0.82/100 py (0.46–1.35) 
 Malignancy 0.20/100 py (0.05–0.51) 0.11/100 py (0.01–0.40) 0.38/100 py (0.15–0.78) 
 Other 0.41/100 py (0.18–0.81) 0.32/100 py (0.12–0.70) 0.38/100 py (0.15–0.78) 
 Unknown 0.05/100 py (0.00–0.28) 0/100 py (0.00–0.00) 0.05/100 py (0.00–0.28) 
Mortality rate ratio 
 All causes 53.0 (36.9–69.1) 19.7 (10.8–28.6) 26.8 (17.8–35.8) 
 Cardiovascular 660.3 (368.1–952.5) 70.0 (14.0–126.0) 19.6 (0.5–38.7) 
 Infections 502.5 (177.5–827.5) 101.8 (14.1–189.5) 352.6 (174.0–531.2) 
 Malignancies 29.2 (12.3–46.1) 18.8 (8.0–29.6) 18.5 (11.5–25.5) 
 Other 17.1 (5.9–28.2) 8.6 (1.0–16.2) 12.8 (3.4–22.2) 
 Unknown 19.9 (0.9–38.9) 0 (0.0–0.0) 10.5 (0.3–20.7) 

*P < 0.05 compared with 1972–89.

When we compared the mortality of RRT patients with that in the general population, the age-adjusted MRR for all causes of death decreased from 53.0 in 1972–89 to 19.7 in 1990–99, but increased again to 26.8 in the last decade (Table 2). However, the trends over time in the MRR were different for various causes of death: the MRR for cardiovascular disease decreased significantly from 660 in 1972–89 to 70 in 1990–99 and decreased further to 20 in 2000–10. Conversely, the MRR trend for infections showed a U-shape; it decreased from 503 in 1972–89 to 102 in 1990–99 and increased again to 353 in 2000–10. The age-adjusted MRR for malignancies did not change over time. In addition, we saw the same trends in MRR for the causes of death when we calculated the MRRs for dialysis patients and transplant recipients separately.

Figure 1a shows the change in the pattern of causes of death per 10-year age category and per time period. It shows a shift from cardiovascular mortality in the younger age categories (Figure 1b) towards infectious mortality in the older age categories over time (Figure 1c and d).

FIGURE 1:

(a) MR/100 person years per age category per ERA. (b) MR/100 person years per era in age category 10–20 years. (c) MR/100 person years per era in age category 20–30 years. (d) MR/100 person years per era in age category 30–40 years.

FIGURE 1:

(a) MR/100 person years per age category per ERA. (b) MR/100 person years per era in age category 10–20 years. (c) MR/100 person years per era in age category 20–30 years. (d) MR/100 person years per era in age category 30–40 years.

A Cox-regression analysis adjusted for background mortality confirmed this change in the pattern. We found a 50% reduction in the risk of overall mortality for 1990–99 when compared with 1972–89 [hazard ratio (HR): 0.50, 95% CI: 0.29–0.86, P = 0.01], but no reduction in overall mortality risk for 2000–10 when compared with 1972–89 (HR: 0.75, 95% CI: 0.47–1.20, P = 0.2; Table 3). After adjustment for expected cardiovascular background mortality, the risk of cardiovascular mortality was 74% lower in 1990–99 than in 1972–89 (HR: 0.26, 95% CI: 0.10–0.66, P = 0.005) and in 2000–10, and it was 91% lower than in 1972–89 (HR: 0.09, 95% CI: 0.02–0.45, P = 0.003; Table 3).

Table 3:

Risk of death for overall, cardiovascular and infectious mortalities in the time period1990–99 and 2000–10 compared with mortality in the period 1972–89

 1990–99 HR (95% CI, P-value) 2000–10 HR (95% CI, P-value) 
All causes of death 
 Unadjusted 0.48 (0.28–0.81, 0.006) 0.79 (0.50–1.26, 0.3) 
 Adjusted for all causes of death general population 0.50 (0.29–0.86, 0.01) 0.75 (0.47–1.20, 0.2) 
Cardiovascular mortality 
 Unadjusted 0.30 (0.12–0.77, 0.01) 0.21 (0.07–0.61, 0.004) 
 Adjusted for cardiovascular mortality general population 0.26 (0.10–0.66, 0.005) 0.09 (0.02–0.45, 0.003) 
Infectious mortality 
 Unadjusted 0.43 (0.15–1.27, 0.1) 1.59 (0.72–3.52, 0.3) 
 Adjusted for infectious mortality general population 0.59 (0.19–1.86, 0.4) 2.12 (0.88–5.11, 0.09) 
 1990–99 HR (95% CI, P-value) 2000–10 HR (95% CI, P-value) 
All causes of death 
 Unadjusted 0.48 (0.28–0.81, 0.006) 0.79 (0.50–1.26, 0.3) 
 Adjusted for all causes of death general population 0.50 (0.29–0.86, 0.01) 0.75 (0.47–1.20, 0.2) 
Cardiovascular mortality 
 Unadjusted 0.30 (0.12–0.77, 0.01) 0.21 (0.07–0.61, 0.004) 
 Adjusted for cardiovascular mortality general population 0.26 (0.10–0.66, 0.005) 0.09 (0.02–0.45, 0.003) 
Infectious mortality 
 Unadjusted 0.43 (0.15–1.27, 0.1) 1.59 (0.72–3.52, 0.3) 
 Adjusted for infectious mortality general population 0.59 (0.19–1.86, 0.4) 2.12 (0.88–5.11, 0.09) 

After adjustment for the expected infectious background mortality, there was a borderline significant trend suggesting an increased risk of death by infections in the last decade 2000–10 when compared with 1972–89 (HR: 2.12, 95% CI: 0.88–5.11, P = 0.09; Table 3). The trend was, however, statistically significant when we compared infectious mortality in 2000–10 with that in 1990–99: the risk of death from infections in the last decade was more than thrice the risk in 1990–99 (HR: 3.22, 95% CI: 1.16–8.99, P = 0.03).

DISCUSSION

In contrast to our expectations, we found a substantial shift from cardiovascular disease to non-cardiovascular disease as the cause of death over the last 10 years in a long-term nationwide follow-up study of patients with paediatric CKD. This occurred while the overall mortality had stabilized over time.

This study is unique in its length of follow-up of patients who started RRT in childhood. Our specific interest in the long-term follow-up of young patients unfortunately hampers the comparison with registry data that are usually presented for overall groups or older age categories with a relatively short follow-up. In addition, time may have affected mortality and causes of death in our cohort in three different fashions. First, there may be an effect of calendar time, as both mortality and causes of death may have changed over time among RRT patients as well as within the general population. Time has also led to a selection of survivors in our cohort and finally, our patients have grown older. We will discuss our results with respect to cardiovascular and infectious death in comparison with other studies, taking these three time dimensions into consideration.

Cardiovascular mortality

Trends over calendar time

As cardiovascular disease turned out to be the most important cause of death in young end stage renal disease (ESRD) patients during the 1990s, several authors have highlighted the huge impact of ESRD and RRT on cardiovascular integrity and function [1, 6–10]. Yet, there are more recent data that confirm a trend of infections gradually replacing cardiovascular disease as the most important cause of death over the last decade. The United States Renal Data System (USRDS) data show a declining burden of cardiovascular mortality among the dialysis patients of all ages over the last years (MR 120/1000 per py) in 2001 to (MR 83/1000 py in 2008) [11] without changes in other causes of death over time (MR 100/1000 py in 1998, 2001 and 2008) [12]. This trend was similar in patients, aged 20–44 years, with a cardiovascular MR declining from 40.5/1000 py in 2001 to 31.3/1000 py in 2008 [11]. Australian and New Zealand Dialysis and Transplantation Registry (ANZDATA) also showed decreasing cardiovascular MRs for all dialysis patients (MR 9.0/100 py in 1992 to 6.4/100 py in 2005), but not among the younger patients aged 35–54 years [13]. In our study, among patients who started RRT at very young age, the decline in cardiovascular deaths over time was far more pronounced than in both the USRDS and ANZDATA studies. This difference may partially be explained by the lack of patients with diabetes mellitus in our cohort, whereas the prevalence of this disease in the RRT population with adult onset of RRT has significantly increased according to both the USRDS and ANZDATA over time. According to the USRDS data, the prevalence of diabetes mellitus as primary disease in the specific age group of our patients increased from 32.5 in 1996 to 42% in 2005, whereas the percentage of diabetes patients aged <55 years in the ANZDATA database even doubled over time from 21.9 in 1992 to 43.3% in 2005 [13, 14]. The absence of increase in cardiovascular deaths in ANZDATA cohort over time with such a concomitant substantial increase in the proportion of diabetic patients with a related severe cardiovascular burden also indicates a change in cardiovascular outcome in dialysis patients.

A possible explanation for the trend of decreased cardiovascular mortality over the last decade could be an increased awareness of the burden of cardiovascular disease in renal patients among physicians and those that may have resulted in better treatment and consequently better survival. If this would be true for our patients, it would also mean that a more aggressive treatment of cardiovascular disease and the prevention of risk factors may be beneficial even in patients who are already on dialysis or living with a functioning graft for a long time. Previous studies have shown that optimized treatment for cardiovascular comorbidity, for example, with Angiotensin-converting-enzyme inhibitors, β-blockers and angiotensin receptor blockers in patients receiving haemodialysis may indeed induce a reduction in both left ventricular hypertrophy and hypertension [15, 16].

The decline in cardiovascular death in our population partly reflects the trend in the western general population. However, according to the MRR, the decline in our RRT patients was much more pronounced than in the general population.

Long-term follow-up and ageing

Long-term outcome data on patients with ESRD are sparse. Most studies exist on transplanted patients. Previous studies in transplanted patients showed a decrease in cardiovascular death at longer follow-up [17, 18]. The USRDS data have been analysed for all-cause, cardiovascular and infectious mortality in patients who received their first transplant at <21 years of age, between 1983 and 2006, and with a follow-up until 2006 [17]. This study showed a significant decrease in cardiovascular mortality in young transplant recipients over time [17, 18]. The risk of all-cause death decreased yearly by 1% after the end of the first year of the first transplant. This decrease in risk was most pronounced for cardiovascular death (16% per year) after the end of the first year of the first transplant [17]. Using the same data, Meier-Kriesche et al. showed a progressive decrease in cardiovascular death rates in transplant recipients >18 years by renal transplant vintage. The MR decreased from 20.8/1000 py 0–3 months after transplantation to 2.8/1000 py 60+ months after transplantation [18]. These findings suggest that transplantation may halt or even reverse the progression of cardiovascular disease. Most of our patients were transplanted, so this certainly will have contributed to a decrease in cardiovascular death in our study. However, we found the same trend in reduction of cardiovascular death among dialysis patients and therefore transplantation cannot be solely responsible for the reduction of cardiovascular death. Moreover, the prevalence of risk factors for cardiovascular death, such as increased vascular stiffness, left ventricular hypertrophy and aortic valve calcification, was high among our patients in 1999, despite the fact that most of them had a long-time lasting functioning graft at that time.

In 2010, all our patients were between 30 and 50 years old. In line with what can be expected in ageing patients, the overall mortality increased over the last decade. However in contrast to that, the cardiovascular disease induced MR decreased with advancing age over the last decade. This could of course have been the result of a selection process and hence of a survivor bias; the sickest patients with cardiovascular comorbidity may have died already before 2000 of cardiovascular disease, leaving the strongest patients for the observation period after 1999. However, as mentioned before, among these survivors, there was a high prevalence of risk factors for cardiac death in 1999 [2]. Furthermore, this trend was only observed over the last decade, whereas cardiovascular mortality did increase with age in our patients, in line with the general population between 1990 and 1999.

Infectious mortality

Trends over calendar time

We found a trend in infectious mortality in three different time periods that suggests an increased risk of death by infections in 2000–10 when compared with 1972–89 and 1990–99.

Infections have for a long time been found to be the second cause of death in patients with ESRD [12]. In line with our data, McDonald and Craig [3] showed a decrease of infectious mortality in patients with paediatric onset of ESRD from 39 between 1963 and 1972 to 16% between 1993 and 2002.

In contrast to our findings, the USRDS data showed a decline of infectious mortality between 1989 and 2010 in ESRD patients, aged 20–44 years. This was accompanied by a similar decline in overall mortality [22]. At the same time, there are data that confirm a more recent tendency towards increase of life-threatening infections in patients with ESRD. The USRDS showed a significant increase in hospitalization due to infection in dialysis patients from 1993 to 2005 [19], as well as in transplanted patients between 1991 and 1998 [20]. The latter may be caused by a more intensive anti-rejection therapy of the last two decades, leading to a more impaired immunity including defective phagocytic function of granulocytes [21]. According to the UK Renal Registry, the number of deaths caused by infections in all patients on RRT has stabilized around 20% between 2000 and 2010. In contrast, the percentage of cardiac deaths decreased from 34 to 22% in this period [22]. The USRDS MRs by infection have also stabilized between 1998 and 2007 for both dialysis and transplanted patients [14]. However, all these reports have the limitation of relatively short follow-up periods.

In dialysis patients, the USRDS reported both an increase in catheter-related infections over time and in catheter-related septicaemia and an overall increasing use of catheters between 1998 and 2007 [23, 23]. In both haemodialysis and peritoneal dialysis patients, catheter-related infections are considered to be the main source of life-threatening infections, leading to peritonitis in peritoneal dialysis and to central venous line-induced septicaemia in haemodialysis.

Our data could not be explained by the trend in the general population, in which infection plays a minor, and over time even a decreasing, role in the cause of death, at least in the western world [5, 14].

Long-term follow-up and ageing

The USRDS data showed that infectious MR in patients who received their first transplant <21 years of age, between 1983 and 2006 and with a follow-up until 2006, did not change at follow-up [17], suggesting that the risk was the same in the first year, as in the years thereafter. This implies that the relative contribution of infectious death has increased over time. Recurrent needle sticks of arteriovenous fistulas or grafts have also been associated with an increased risk of infections [21]. Jean et al. [24] found that a high incidence of catheter-related bacteraemia, and bacteraemic catheters were more often observed in patients with longer catheter survival time.

There are no data that support the becoming of age of our patients as a potential factor for an increased risk of fatal infections. Previously, it had been found that, in transplanted patients, very young as well as very old patients were particularly prone to dying of infections [20]. The oldest patient of our cohort was 50 years old in 2010, and very few children have been transplanted at a very young age. This may explain why we found that the risk of infectious death was constant across all age groups.

LIMITATIONS

The establishment of the exact cause of death in patients with a complicated course of disease, as was often the case in our patients, can be difficult. In order to cope with this problem, three observers independently determined the cause of death based on detailed descriptions of all available chart information covering the period around the patient's time of death. After assessment of interobserver variability, consensus was achieved by discussion.

CONCLUSION

In conclusion, we show that there is a substantial shift in causes of death after long-term RRT since childhood. Cardiovascular mortality decreased significantly in the last 10 years compared with the period 1972–99, and infectious mortality increased (although not significantly). A possible reason for the significant decreased risk of cardiovascular mortality could be the awareness of the cardiovascular burden in these patients that urged a strict cardiovascular management of these patients. Physicians should on the other hand be aware of the emerging burden of potentially fatal infections in these patients and take precautions for prevention.

SUPPLEMENTARY DATA

Supplementary data are available online athttp://ndt.oxfordjournals.org.

ACKNOWLEDGEMENTS

We are grateful to the Department of Medical Informatics and to all participating centres in the LERIC study with special thanks to the participating nephrologists; Dr J.M.A. Ampting, Dr A.J. Apperloo, Dr C.H. Beerenhout, Dr F.J. Bemelman, Dr M. Boekhout, Dr P.J.M. van der Boog, Dr M.H.L. Christiaans, Dr S.H.A. Diepeveen, M.A. van den Dorpel, Dr A van Es, Dr W.J. Fagel, Dr B.A.Th.F. Gabreels, Dr A.B.M. Geers, Dr P.G.G. Gerlag, Dr E.C. Hagen, Dr M. den Hartog, Dr R.J. Hene, Dr J.J Homan van der Heide, Prof. Dr A.J. Hoitsma, Dr M. Huisman, Dr B.C. van Jaarsveld, Dr K. Jie, Dr G.M.T. de Jong, Dr W.A.H. Koning-Mulder, Prof. Dr M.P. Kooistra, Dr W.H.M. van Kuijk, Dr A.G. Lieverse, Dr R.R.H. Nap, Dr M.J. Nubé, Dr K.J. Parlevliet, Dr E.J. Roodnat, Dr van Schie, Dr M.A.J. Seelen, Dr H.E. Sluiter, Dr C.R. Susanto, Dr R.M. Valentijn, Dutch Kidney Foundation and Department of Medical Informatics, Academic Medical Centre Amsterdam. This study was performed as part of the LERIC follow-up study, which is mainly funded by the Dutch Kidney Foundation. The funder had no role in the design and conduct of the study, data gathering or interpretation, in the preparation of the manuscript or in the decision to submit the report for publication.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES

1
Groothoff
JW
Gruppen
MP
Offringa
M
, et al.  . 
Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study
Kidney Int
 , 
2002
, vol. 
61
 (pg. 
621
-
629
)
2
Groothoff
JW
Lilien
MR
van de Kar
NC
, et al.  . 
Cardiovascular disease as a late complication of end-stage renal disease in children
Pediatr Nephrol
 , 
2005
, vol. 
20
 (pg. 
374
-
379
)
3
McDonald
SP
Craig
JC
Long-term survival of children with end-stage renal disease
N Engl J Med
 , 
2004
, vol. 
350
 (pg. 
2654
-
2662
)
4
Oh
J
Wunsch
R
Turzer
M
, et al.  . 
Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure
Circulation
 , 
2002
, vol. 
106
 (pg. 
100
-
105
)
5
Statistics Netherlands
 
www.cbs.nl September 2012, date last accessed
6
de Jager
DJ
Grootendorst
DC
Jager
KJ
, et al.  . 
Cardiovascular and noncardiovascular mortality among patients starting dialysis
JAMA
 , 
2009
, vol. 
302
 (pg. 
1782
-
1789
)
7
Mitsnefes
MM
Cardiovascular morbidity and mortality in children with chronic kidney disease in North America: lessons from the USRDS and NAPRTCS databases
Perit Dial Int
 , 
2005
, vol. 
25
 
Suppl 3
(pg. 
S120
-
S122
)
8
Parekh
RS
Carroll
CE
Wolfe
RA
, et al.  . 
Cardiovascular mortality in children and young adults with end-stage kidney disease
J Pediatr
 , 
2002
, vol. 
141
 (pg. 
191
-
197
)
9
van der Heijden
BJ
van Dijk
PC
Verrier-Jones
K
, et al.  . 
Renal replacement therapy in children: data from 12 registries in Europe
Pediatr Nephrol
 , 
2004
, vol. 
19
 (pg. 
213
-
221
)
10
Wright
J
Hutchison
A
Cardiovascular disease in patients with chronic kidney disease
Vasc Health Risk Manag
 , 
2009
, vol. 
5
 (pg. 
713
-
722
)
11
Atlas of End-Stage Renal Disease in the United States 2011. United States Renal Data System, Annual Report. Volume 2: End-Stage Renal Disease; Chapter 5; Mortality; 228
12
Atlas of End-stage Renal Disease in the United States 2011. United States Renal Data System, Annual Report. Volume 2: End-Stage Renal Disease; Chapter 4; Cardiovascular Disease in Patients with End-Stage Renal Disease; 221
13
Roberts
MA
Polkinghorne
KR
McDonald
SP
, et al.  . 
Secular trends in cardiovascular mortality rates of patients receiving dialysis compared with the general population
Am J Kidney Dis
 , 
2011
, vol. 
58
 (pg. 
64
-
72
)
14
Atlas of End-Stage Renal Disease in the United States 2011. United States Renal Data System, Annual Report. Volume 2: End-Stage Renal Disease; Chapter 2; Clinical Indicators and Preventive Care; 201
15
Hampl
H
Hennig
L
Rosenberger
C
, et al.  . 
Effects of optimized heart failure therapy and anemia correction with epoetin beta on left ventricular mass in hemodialysis patients
Am J Nephrol
 , 
2005
, vol. 
25
 (pg. 
211
-
220
)
16
Ulinski
T
Genty
J
Viau
C
, et al.  . 
Reduction of left ventricular hypertrophy in children undergoing hemodialysis
Pediatr Nephrol
 , 
2006
, vol. 
21
 (pg. 
1171
-
1178
)
17
Foster
BJ
Dahhou
M
Zhang
X
, et al.  . 
Change in mortality risk over time in young kidney transplant recipients
Am J Transplant
 , 
2011
, vol. 
11
 (pg. 
2432
-
2442
)
18
Meier-Kriesche
HU
Schold
JD
Srinivas
TR
, et al.  . 
Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease
Am J Transplant
 , 
2004
, vol. 
4
 (pg. 
1662
-
1668
)
19
Atlas of End-Stage Renal Disease in the United States 2008. United States Renal Data System, Annual Report. Volume 2: End-Stage Renal Disease; Chapter 6; Morbidity and Mortality; 108
20
Dharnidharka
VR
Caillard
S
Agodoa
LY
, et al.  . 
Infection frequency and profile in different age groups of kidney transplant recipients
Transplantation
 , 
2006
, vol. 
81
 (pg. 
1662
-
1667
)
21
Vanholder
R
Ringoir
S
Infectious morbidity and defects of phagocytic function in end-stage renal disease: a review
J Am Soc Nephrol
 , 
1993
, vol. 
3
 (pg. 
1541
-
1554
)
22
UK Renal Registry
The Fourteenth Annual Report
 
23
United States Renal Data System
 
www.usrds.org September 2012, date last accessed)
24
Jean
G
Charra
B
Chazot
C
, et al.  . 
Risk factor analysis for long-term tunneled dialysis catheter-related bacteremias
Nephron
 , 
2002
, vol. 
91
 (pg. 
399
-
405
)

Comments

1 Comment
Specific mortality risk in patients with renal replacement therapy since childhood
24 October 2013
Tomoyuki Kawada

Vogelzang et al. reported the risk assessment of specific mortality in patients with renal replacement therapy since childhood [1]. They adopted the Cox proportional hazards model by adjusting for age and gender, and clarified the shift in cause of death from cardiovascular disease to infectious disease.

I have two concerns: First, there is a report that initiation of dialysis treatment before 5 years, compared with thereafter, shows poor prognosis for mortality, although the prognosis showed an improvement in the last two decades [2]. Samuel et al. also conducted a follow-up study for dialysis children with end-stage renal disease [3], and the overall survival was poorest among those who started dialysis at age <1 year. From these reports, appropriate adjustment by pre-treatment information before renal replacement therapy should be conducted for their analysis.

Second, the authors handled 249 patients, who received renal replacement therapy before the age of 15. Among them, 42 died between 1972 and 1989, 21 between 1990 and 1999 and 34 between 2000 and 2010. In the last decade, 4 patients died from cardiovascular disease, 15 patients from infections, 7 patients from malignancies, 7 patients from other causes and 1 patient from unknown cause, which was presented in their Appendix 1. These data can be calculated by using information in their Table 2. From 1972 to 1989 (1990 to 1999), 19 (7) patients died from cardiovascular disease, 10 (6) patients from infections, 4 (2) patients from malignancies, 8 (6) patients from other causes and 1 (0) patient from unknown cause. About the appropriate number of independent variables, the number of events per independent variable in Cox regression analysis should be 10 or more to keep statistical power [4]. Although Vogelzang et al. used age and gender for the adjustment of HRs, the number of cardiovascular events was 30 in total, and the number of independent variables is limited to 3. As the number of events by infection was 31, the number of independent variables is also limited to 3. As they calculate HRs by excluding data in the period from 1990 to 99 or from 2000 to 2010, the number of independent variables should be limited to 3. This means that a stable estimate with sufficient statistical power cannot be conducted for their analysis, and a decreasing trend from specific mortality in patients with renal replacement therapy in the last decade should be handled with caution.

There is a report that cardiovascular care for adolescents with kidney disease, including chronic kidney disease and ESKD, relates to their future cardiovascular mortality [5]. The significance of preventive care for cardiovascular disease including lifestyle modifications should also be considered, although the prevalence of cardiovascular mortality showed a decreasing trend.

References 1. Vogelzang JL, van Stralen KJ, Jager KJ et al. Trend from cardiovascular to non-cardiovascular late mortality in patients with renal replacement therapy since childhood. Nephrol Dial Transplant 2013;28:2082-2089.

2. Mitsnefes MM, Laskin BL, Dahhou M et al. Mortality risk among children initially treated with dialysis for end-stage kidney disease, 1990-2010. JAMA 2013;309:1921-1929.

3. Samuel SM, Tonelli MA, Foster BJ et al. Survival in pediatric dialysis and transplant patients. Clin J Am Soc Nephrol 2011;6:1094-1099.

4. Concato J, Peduzzi P, Holford TR et al. Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol 1995;48:1495-1501.

5. Hooper DK, Williams JC, Carle AC et al. The quality of cardiovascular disease care for adolescents with kidney disease: a Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol 2013;28:939-949.

Conflict of Interest:

None declared

Submitted on 24/10/2013 8:00 PM GMT